Disease associated prion protein oligomers inhibit the 26S proteasome

The rogue prion proteins responsible for diseases like BSE and vCJD can destroy brain cells by blocking the protein recycling process that helps keep cells healthy.

An international group of scientists, led by Dr Sarah Tabrizi of University College London's Institute of Neurology, has now discovered which part of the structure of the protein it is that creates this effect and that even a tiny number of rogue prions are toxic enough to stop a cell's protein clearing machinery and cause disease.

Together with colleagues at the Medical Research Council Prion Unit, Dr Tabrizi's team monitored the action of rogue prion proteins on the brain cells of mice genetically designed for the task. The brain cells of these mice produce a protein that glows green when the cell's recycling machinery is failing allowing scientists to assess how the system has been affected. Their results are published in Molecular Cell .

A comparison of mouse nerve cells infected with and without prions, the green glowing patches develop as the cell's recycling machinery fails in prion infected cells.

‘‘When we looked closely at the interaction between rogue prions and the protein recycling process in healthy cells, it was clear that just three or four molecules, a really tiny concentration of prions, is enough to disrupt the system and damage the brain cell'' explains Dr Tabrizi. ‘‘This suggests there is a direct relationship between destruction of brain cells and blockage of protein recycling. Exactly how rogue prion proteins destroy brain cells is still a puzzle, but this research is evidence that blocking the cell's protein recycling machinery is one way prion infection can cause disease.''

The protein recycling system is crucial to a healthy cell because it protects it from a potentially toxic build-up of faulty proteins. The process itself is known as the ubiquitin-proteasome system or UPS. The idea to investigate the cell's protein recycling system came from previous research by Dr Tabrizi and her colleagues. They found that if prion infected nerve cells are treated with a drug that causes the UPS to be stressed, abnormally shaped prion proteins build up more quickly and eventually kill the cell. These collections of abnormally shaped proteins are a feature of many prion diseases and can be clearly seen in the brains of prion-infected mice.

Commenting on this research, Professor John Collinge, Director of the MRC Prion Unit said:

‘‘Understanding how rogue prions kill cells is crucial to learning more about the prion diseases that remain a major concern for public and animal health following the BSE epidemic in UK cattle and the emergence of its human counterpart variant CJD. This work forms part of a major research strategy at the MRC Prion Unit to translate basic research findings into potential treatments in the years ahead. The underlying mechanism by which rogue prion proteins disrupt the UPS may be of wider relevance in understanding how misshaped proteins cause other disorders too, like Alzheimer's disease.''

Original research paper: Disease associated prion protein oligomers inhibit the 26S proteasome by Kristiansen et al published in Molecular Cell on 27 th April

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